Why does my shoulder hurt? A review of the neuroanatomical and biochemical basis of shoulder pain Benjamin John Floyd Dean, Stephen Edward Gwilym, Andrew Jonathan Carr Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Botnar Musculoskeletal Research Unit, Oxford University, Oxford, Oxon, UK Correspondence to Benjamin John Floyd Dean, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Botnar Research Centre, Institute of Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Windmill Road, Oxford OX3 7LD, UK; [email protected]. ac.uk Received 19 June 2012 Revised 8 January 2013 Accepted 22 January 2013 To cite: Dean BJF, Gwilym SE, Carr AJ. Br J Sports Med Published Online First: [ please include Day Month Year] doi:10.1136/ bjsports-2012-091492 ABSTRACT If a patient asks ‘why does my shoulder hurt?’ the conversation will quickly turn to scientific theory and sometimes unsubstantiated conjecture. Frequently, the clinician becomes aware of the limits of the scientific basis of their explanation, demonstrating the incompleteness of our understanding of the nature of shoulder pain. This review takes a systematic approach to help answer fundamental questions relating to shoulder pain, with a view to providing insights into future research and novel methods for treating shoulder pain. We shall explore the roles of (1) the peripheral receptors, (2) peripheral pain processing or ‘nociception’, (3) the spinal cord, (4) the brain, (5) the location of receptors in the shoulder and (6) the neural anatomy of the shoulder. We also consider how these factors might contribute to the variability in the clinical presentation, the diagnosis and the treatment of shoulder pain. In this way we aim to provide an overview of the component parts of the peripheral pain detection system and central pain processing mechanisms in shoulder pain that interact to produce clinical pain. INTRODUCTION: A VERY BRIEF HISTORY OF PAIN SCIENCE ESSENTIAL FOR CLINICIANS The nature of pain, in general, has been a subject of much controversyover the past century. In the 17th century Descartes’ theory 1 proposed that the inten- sity of pain was directly related to the amount of associated tissue injury and that pain was processed in one distinct pathway. Many earlier theories relied upon this so-called ‘dualist’ Descartian philosophy, seeing pain as the consequence of the stimulation of a ‘specific’ peripheral pain receptor in the brain. In the 20th century a scientific battle between two opposing theories ensued, namely specificity theory and pattern theory. The Descartian ‘specificity theory’ saw pain as a specific separate modality of sensory input with its own apparatus, while ‘pattern theory’ felt that pain resulted from the intense stimulation of non-specific receptors. 2 In 1965, Wall and Melzack’s 3 gate theory of pain provided evi- dence for a model in which pain perception was modulated by both sensory feedback and the central nervous system. Another huge advance in pain theory at around the same time saw the discovery of the specific mode of actions of the opioids. 4 Subsequently, recent advances in neuroimaging and molecular medicine have vastly expanded our overall understanding of pain. So how does this relate to shoulder pain? Shoulder pain is a common clinical problem, and a robust understanding of the way in which pain is processed by the body is essential to best diagnose and treat a patient’s pain. Advances in our knowl- edge of pain processing promise to explain the mis- match between pathology and the perception of pain, they may also help us explain why certain patients fail to respond to certain treatments. BASIC BUILDING BLOCKS OF PAIN Peripheral sensory receptors: the mechanoreceptor and the ‘nociceptor’ There are numerous types of peripheral sensory receptors present in the human musculoskeletal system. 5 They may be classified based on their func- tion (as mechanoreceptors, thermoreceptors or nociceptors) or morphology (free nerve endings or different types of encapsulated receptors). 5 The dif- ferent types of receptor can then be further subclas- sified based on the presence of certain chemical markers. There are significant overlaps between dif- ferent functional classes of receptor, for example between the mechanoreceptor and nociceptor, and this has the potential to cause significant confusion. For this reason it is absolutely vital to understand that there is no universally accepted receptor classi- fication system and that receptors are best seen as a continuum, in which the artificial boundaries between different receptor types are somewhat arbitrary and fluid. Despite this, it is still worth- while considering how sensory receptors may be classified in greater detail. Sensory receptors are supplied by afferent nerves of varying sizes, degrees of myelination and con- duction velocities. On this basis sensory nerves can be simply divided into three main groups (conduc- tion velocity given in brackets): thick diameter myelinated group II or Aβ fibres (>20 m/s), small diameter myelinated group III or Aδ fibres (2.5– 20 m/s) and unmyelinated group IV or C fibres (<2.5 m/s). 6 Receptors are sometimes referred to simply by the characteristics of the nerves that innervates them, for example ‘ Aδ nerve endings’. This description makes no reference to a receptor’s other specific characteristics as outlined above and described in greater detail in the following. Receptors that respond preferentially to noxious stimuli and those that have a high threshold to the adequate stimulus are termed ‘nociceptors’. 7 Nociceptors may respond to multiple energy forms such as thermal, mechanical and chemical stimuli. Nociceptors can be comprehensively subclassified based on four criteria: myelination of nerve supply (unmyelinated C fibres versus myelinated Aδ fibres), modalities of stimulus that evoke a response, response characteristics and distinctive chemical Dean BJF, et al. Br J Sports Med 2013;00:1–12. doi:10.1136/bjsports-2012-091492 1 Review BJSM Online First, published on February 21, 2013 as 10.1136/bjsports-2012-091492 Copyright Article author (or their employer) 2013. Produced by BMJ Publishing Group Ltd under licence. group.bmj.com on November 8, 2016 - Published by http://bjsm.bmj.com/ Downloaded from
Transcript
Why does my shoulder hurt? A review of theneuroanatomical and biochemical basis ofshoulder painBenjamin John Floyd Dean, Stephen Edward Gwilym, Andrew Jonathan Carr
Nuffield Department ofOrthopaedics, Rheumatologyand Musculoskeletal Sciences(NDORMS), BotnarMusculoskeletal Research Unit,Oxford University, Oxford,Oxon, UK
Correspondence toBenjamin John Floyd Dean,Nuffield Department ofOrthopaedics, Rheumatologyand Musculoskeletal Sciences(NDORMS), Botnar ResearchCentre, Institute ofMusculoskeletal Sciences,Nuffield Orthopaedic Centre,Windmill Road,Oxford OX3 7LD, UK;[email protected]
Received 19 June 2012Revised 8 January 2013Accepted 22 January 2013
To cite: Dean BJF,Gwilym SE, Carr AJ. Br JSports Med Published OnlineFirst: [please include DayMonth Year] doi:10.1136/bjsports-2012-091492
ABSTRACTIf a patient asks ‘why does my shoulder hurt?’ theconversation will quickly turn to scientific theory andsometimes unsubstantiated conjecture. Frequently, theclinician becomes aware of the limits of the scientificbasis of their explanation, demonstrating theincompleteness of our understanding of the nature ofshoulder pain. This review takes a systematic approachto help answer fundamental questions relating toshoulder pain, with a view to providing insights intofuture research and novel methods for treating shoulderpain. We shall explore the roles of (1) the peripheralreceptors, (2) peripheral pain processing or ‘nociception’,(3) the spinal cord, (4) the brain, (5) the location ofreceptors in the shoulder and (6) the neural anatomy ofthe shoulder. We also consider how these factors mightcontribute to the variability in the clinical presentation,the diagnosis and the treatment of shoulder pain. In thisway we aim to provide an overview of the componentparts of the peripheral pain detection system and centralpain processing mechanisms in shoulder pain thatinteract to produce clinical pain.
INTRODUCTION: A VERY BRIEF HISTORY OFPAIN SCIENCE ESSENTIAL FOR CLINICIANSThe nature of pain, in general, has been a subject ofmuch controversy over the past century. In the 17thcentury Descartes’ theory1 proposed that the inten-sity of pain was directly related to the amount ofassociated tissue injury and that pain was processedin one distinct pathway. Many earlier theories reliedupon this so-called ‘dualist’ Descartian philosophy,seeing pain as the consequence of the stimulationof a ‘specific’ peripheral pain receptor in the brain.In the 20th century a scientific battle between twoopposing theories ensued, namely specificity theoryand pattern theory. The Descartian ‘specificitytheory’ saw pain as a specific separate modality ofsensory input with its own apparatus, while ‘patterntheory’ felt that pain resulted from the intensestimulation of non-specific receptors.2 In 1965, Walland Melzack’s3 gate theory of pain provided evi-dence for a model in which pain perception wasmodulated by both sensory feedback and the centralnervous system. Another huge advance in paintheory at around the same time saw the discovery ofthe specific mode of actions of the opioids.4
Subsequently, recent advances in neuroimaging andmolecular medicine have vastly expanded ouroverall understanding of pain.So how does this relate to shoulder pain?
Shoulder pain is a common clinical problem, and arobust understanding of the way in which pain is
processed by the body is essential to best diagnoseand treat a patient’s pain. Advances in our knowl-edge of pain processing promise to explain the mis-match between pathology and the perception ofpain, they may also help us explain why certainpatients fail to respond to certain treatments.
BASIC BUILDING BLOCKS OF PAINPeripheral sensory receptors: themechanoreceptor and the ‘nociceptor’There are numerous types of peripheral sensoryreceptors present in the human musculoskeletalsystem.5 They may be classified based on their func-tion (as mechanoreceptors, thermoreceptors ornociceptors) or morphology (free nerve endings ordifferent types of encapsulated receptors).5 The dif-ferent types of receptor can then be further subclas-sified based on the presence of certain chemicalmarkers. There are significant overlaps between dif-ferent functional classes of receptor, for examplebetween the mechanoreceptor and nociceptor, andthis has the potential to cause significant confusion.For this reason it is absolutely vital to understandthat there is no universally accepted receptor classi-fication system and that receptors are best seen as acontinuum, in which the artificial boundariesbetween different receptor types are somewhatarbitrary and fluid. Despite this, it is still worth-while considering how sensory receptors may beclassified in greater detail.Sensory receptors are supplied by afferent nerves
of varying sizes, degrees of myelination and con-duction velocities. On this basis sensory nerves canbe simply divided into three main groups (conduc-tion velocity given in brackets): thick diametermyelinated group II or Aβ fibres (>20 m/s), smalldiameter myelinated group III or Aδ fibres (2.5–20 m/s) and unmyelinated group IV or C fibres(<2.5 m/s).6 Receptors are sometimes referred tosimply by the characteristics of the nerves thatinnervates them, for example ‘Aδ nerve endings’.This description makes no reference to a receptor’sother specific characteristics as outlined above anddescribed in greater detail in the following.Receptors that respond preferentially to noxious
stimuli and those that have a high threshold to theadequate stimulus are termed ‘nociceptors’.7
Nociceptors may respond to multiple energy formssuch as thermal, mechanical and chemical stimuli.Nociceptors can be comprehensively subclassifiedbased on four criteria: myelination of nerve supply(unmyelinated C fibres versus myelinated Aδ fibres),modalities of stimulus that evoke a response,response characteristics and distinctive chemical
Dean BJF, et al. Br J Sports Med 2013;00:1–12. doi:10.1136/bjsports-2012-091492 1
Review BJSM Online First, published on February 21, 2013 as 10.1136/bjsports-2012-091492
Copyright Article author (or their employer) 2013. Produced by BMJ Publishing Group Ltd under licence.
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markers.8 On a molecular basis, nociceptors can be either pepti-dergic or non-peptidergic based on whether peptides areexpressed in their dorsal root ganglion cells.8 The peptidesexpressed include substance P (SP), calcitonin gene-relatedpeptide (CGRP) and somatostatin. The subclassification of noci-ceptors is complex; furthermore, they have a degree of func-tional and chemical plasticity which ensures that their thresholdand responsiveness, as well as the efficacy of their synaptic con-tacts, are regulated to reflect changes produced by activity,inflammation and axonal injury.8
The second form of receptors is the mechanoreceptor whichconveys information about the mechanical stimuli to the centralnervous system. The main innocuous-touch receptors include(skin stimulus is in brackets): Meissner corpuscles (dynamicdeformation), Merkel cell–neurite complexes (indentationdepth), Pacinian/lamellar corpuscles (vibration), Ruffini recep-tors/endings/corpuscles (stretch) and free nerve endings (touch).The term ‘proprioceptor’ is used to describe a mechanorecep-tor’s role which is that of responding to the mechanical variablesassociated with muscles and joints.9 Proprioceptors includemuscle spindles, Golgi tendon organs and Ruffini-type receptors.
Mechanoreceptors can be classified as low-threshold mechan-oreceptors (LTMs), thus called because they respond to innocu-ous mechanical forces, or high-threshold mechanoreceptors(HTMs), thus called because they are excited only by greatermechanical forces. As with nociceptors, different types ofmechanoreceptors are associated with specific afferent nervetypes. Undoubtedly, there is a significant degree of crossoverbetween the properties of both nociceptors and mechanorecep-tors, demonstrated by the fact that HTMs can also be describedas nociceptors.10 11 Certainly, creating any absolute divisionbetween the two is somewhat artificial and potentially mislead-ing, especially given the plasticity of the receptor characteristics.
Generally, mechanoreceptors supplied by Aβ nerve endingsare LTMs, while those supplied by Aδ nerve endings may beeither HTMs or LTMs. HTMs supplied by Aδ nerve endingsand the majority of C fibre nerve endings may be termed noci-ceptors. Schaible and Grubb6 have studied the mechanosensitiv-ity of different fibre types (Aβ, Aδ and C) supplying the cat kneejoint. They found that most Aβ nerve endings were activated byinnocuous stimuli and hence could be termed LTMs. A muchhigher percentage of Aδ and C fibre nerve endings were insensi-tive to innocuous stimuli (50% and 70%, respectively) andcould be classified as HTMs. Many LTMs fire in the innocuousrange but have a far stronger response in the noxious range,demonstrating the dynamic complexity of their function.
A typical joint nerve is innervated by thick diameter myelin-ated Aβ, small diameter myelinated Aδ and a high proportion(circa 80%) of unmyelinated C fibres. C fibres are further subdi-vided into either sensory afferents or sympathetic efferents, with
about 50% of each.6 Muscle nerves consist of axons frommotor neurons, sensory neurons and postganglionic sympatheticneurons. Each of these nerve types may end in a number of dif-ferent ‘receptors’ as described hereinbefore. Freeman andWyke12 classified the different types of articular nerve endingsbased on their pioneering work in the knee joints of cats in1967, these being summarised in table 1. They classified the dif-ferent endings as types I, II, III and IV on a morphological andfunctional basis. Some of the eponymous terms used to describereceptors of different types are included in table 1, for example‘Ruffini ending’ and ‘Golgi-Mazzoni body’. Other authors havesince modified the eponymous terms mentioned in Freeman andWyke’s classification system.13
Articular Aβ fibres terminate as corpuscular endings of theRuffini, Golgi and Pacini types in the fibrous capsule, articularligaments, menisci and adjacent periosteum.14 While articularAδ and C fibres terminate as non-corpuscular or free nerveendings in the fibrous capsule, adipose tissue, ligaments,menisci, periosteum and synovium. The cartilage is not inner-vated. In muscles, thick myelinated afferents terminate as orga-nised endings such as muscle spindles and tendon organs, whileAδ and C fibres terminate as free nerve endings. The receptortypes and innervation specifically relating to the shoulder willbe explored in greater detail in sections ‘Where are these recep-tors located in the shoulder?’ and ‘Neural anatomy of theshoulder’.
Peripheral pain processing: ‘nociception’Tissue injury involves a variety of inflammatory mediators beingreleased by damaged cells including bradykinin, histamine,5-hydroxytryptamine, ATP, nitric oxide and certain ions (K+
and H+). The activation of the arachidonic acid pathway leadsto the production of prostaglandins, thromboxanes and leuko-trienes. Cytokines, including the interleukins and tumor necrosisfactor α, and neurotrophins, such as nerve growth factor(NGF), are also released and are intimately involved in thefacilitation of inflammation.15 Other substances such as excita-tory amino acids (glutamate) and opioids (endothelin-1) havealso been implicated in the acute inflammatory response.16 17
Some of these agents may directly activate nociceptors, whileothers bring about the recruitment of other cells which thenrelease further facilitatory agents.18 This local process resultingin the increased responsiveness of nociceptive neurons to theirnormal input and/or the recruitment of a response to normallysubthreshold inputs is termed ‘peripheral sensitisation’. Figure 1summarises some of the key mechanisms involved.
NGF and the transient receptor potential cation channelsubfamily V member 1 (TRPV1) receptor have a symbiotic rela-tionship when it comes to inflammation and nociceptor sensi-tisation. The cytokines produced in inflamed tissue result in an
Table 1 The Freeman and Wyke classification of joint nerve endings
Type Morphology LocationDiameter of parentfibre (mm)
Principle functionalcharacteristics Eponymous or descriptive terms
I Globular or ovoid corpuscles, finecapsule, in clusters of 3–6
increase in NGF production.19 NGF stimulates the release ofhistamine and serotonin (5-HT3) by mast cells, and also sensi-tises nociceptors, possibly altering the properties of Aδ fibressuch that a greater proportion become nociceptive. The TRPV1receptor is present in a subpopulation of primary afferent fibresand is activated by capsaicin, heat and protons. The TRPV1receptor is synthesised in the cell body of the afferent fibre, andis transported to both the peripheral and central terminals,where it contributes to the sensitivity of nociceptive afferents.Inflammation results in NGF production peripherally whichthen binds to the tyrosine kinase receptor type 1 receptor onthe nociceptor terminals, NGF is then transported to the cellbody where it leads to an up regulation of TRPV1 transcriptionand consequently increased nociceptor sensitivity.19 20 NGF andother inflammatory mediators also sensitise TRPV1 through adiverse array of secondary messenger pathways. Many otherreceptors including cholinergic receptors, γ-aminobutyric acid(GABA) receptors and somatostatin receptors are also thoughtto be involved in peripheral nociceptor sensitivity.
A large number of inflammatory mediators have been specific-ally implicated in shoulder pain and rotator cuff disease.21–25
While some chemical mediators directly activate nociceptors,most lead to changes in the sensory neuron itself rather thandirectly activating it. These changes may be early post-translational or delayed transcription dependent. Examples ofthe former are changes in the TRPV1 receptor or in voltage-gated ion channels resulting from the phosphorylation ofmembrane-bound proteins. Examples of the latter include theNGF-induced increase in TRV1 channel production and thecalcium-induced activation of intracellular transcription factors.
Primary hyperalgesia and peripheral sensitisationPrimary hyperalgesia is defined as hyperalgesia, or hypersensitiv-ity, at the site of injury (the primary zone).26 Several mediatorsmay lead to the sensitisation of a nociceptor and therefore playa role in primary hyperalgesia.27 Primary hyperalgesia relates toboth heat and mechanical stimuli.28 The hyperalgesia to heat
stimuli that occurs at the site of injury is thought to be owing tothe sensitisation of primary afferent nociceptors, that is, periph-eral sensitisation. However, the hyperalgesia to mechanicalstimuli at the site of injury results from not only peripheral sen-sitisation, but probably from central sensitisation as well.29
Different types of mechanical hyperalgesia have been described:one type is hyperalgesia to light touch or ‘allodynia’, another is‘punctate’ hyperalgesia and a third is termed ‘pressure’ or‘impact’ hyperalgesia.30 It must be remembered that the acutepresence of both allodynia and ‘punctate’ hyperalgesia at thesite of injury may be demonstrative of a completely normal painresponse, in response to acute injury for example, sunburntskin. A lowered threshold to stimulation, an increased responseto suprathreshold stimuli and the expansion of receptive fieldsare all ways in which the nociceptor sensitisation of primaryhyperalgesia may be manifest.31
Secondary hyperalgesia and central sensitisationSecondary hyperalgesia is defined as hyperalgesia outside theoriginal zone of injury and relates to the sensory response tomechanical stimuli only.28 The localised activation of nocicep-tors leads to a ‘flare response’ outside the zone of initial injurythrough the spreading chemical activation of adjacent nocicep-tors. However, La Motte et al32 demonstrated that proximalnerve blocks prevent the development of secondary hyperalge-sia, indicating that higher pathways must be involved and thatthe flare response cannot fully account for secondary hyperalge-sia. The flare response and secondary hyperalgesia have alsobeen shown to be distinct entities for several reasons: the zoneof secondary hyperalgesia is generally larger than the ‘flare’,they can exist independently, and secondary hyperalgesia doesnot migrate across the body’s midline, whereas flare does.32
Peripheral sensitisation cannot adequately account for secondaryhyperalgesia; hence the central nervous system must have a keyrole to play in this phenomenon.27 33 It is clear that the periph-eral signal for pain is not purely driven by nociceptors; underpathological circumstances other receptors types, which are
normally associated with the sensation of touch, acquire theability to elicit pain.33 34 This applies to neuropathic pain aswell as to acute secondary hyperalgesia.
The term ‘central sensitisation’ is used to describe the phe-nomenon whereby central pain-signalling neurons becomehypersensitive to the input of LTMs.34 ‘Central sensitisation’may also be more generally described as ‘an amplification ofneural signalling within the CNS that elicits pain hypersensitiv-ity’.35 Secondary hyperalgesia (and therefore central sensitisa-tion) is seen in many clinical situations including the acutelyinflamed joint,36 the arthritic knee37 and the painful shoulder.38
Two distinct forms of secondary hyperalgesia have beenobserved: punctuate and light touch hyperalgesia (allodynia).Punctate hyperalgesia is thought to be different from light touchhyperalgesia for several reasons: the area of punctuate hyper-algesia is larger than that of light touch hyperalgesia and lighttouch hyperalgesia post capsaicin is significantly shorter livedthan punctate hyperalgesia. Light touch hyperalgesia32 andpunctate hyperalgesia33 both appear to be mediated by LTMs.Ziegler et al39 used an intradermal capsaicin model to show thatpunctuate hyperalgesia was mediated by smaller myelinatedfibres than light touch hyperalgesia. Certainly, the central sensi-tisation is induced by unmyelinated C fibre nociceptors, but theexact higher mechanisms have yet to be fully determined40: it islikely that the sensitisation of nociceptive neurons in the dorsalhorn of the spinal cord are involved, although a novel presynap-tic model has been proposed by Cervero.41 The way in whichthe facilitated pathways (myelinated A fibres) are separate fromthe facilitating pathways (unmyelinated C fibres) in this processis called a ‘heterosynaptic’ form of facilitation.29 Heterosynapticfacilitation is distinct to ‘homosynaptic’ facilitation, an exampleof the latter being ‘wind up’, that is, the temporal summation topunctuate stimuli in the zone of capsaicin injection. In ‘homosy-naptic’ facilitation, the events responsible for triggering synapticstrengthening occur at the same synapse that is being strength-ened. In ‘heterosynaptic’ facilitation synaptic strengtheningbetween a presynaptic and a postsynaptic cell may occur as aresult of the firing of a third neuron, a modulatory interneuron,whose terminals end on and regulate the strength of the specificsynapse.42
Spinal cordThe spinal dorsal horn receives inputs from a wide variety ofprimary afferent fibres including those from nociceptors andmechanoreceptors.40 Primary afferents generally use glutamateas their principal neurotransmitter and form excitatory (glutami-nergic) synapses with the neurons in the dorsal horn.40 Theprimary afferent fibres may synapse with two broad types ofneuron: projection cells which travel in rostral parts of thespinal cord to the higher brain centres and interneurons whichremain in the spinal cord and contribute to local neuronal cir-cuits. Interneurons can be either inhibitory, using GABA/glycineas their neurotransmitter, or excitatory (glutaminergic).43 Theintrathecal administration of drugs that antagonise GABA/glycine receptors can cause allodynia, suggesting that one keyfunction of inhibitory interneurons is to suppress the activity oftactile afferents so that they do not normally elicit pain. Thedorsal horn also receives an important descending input fromhigher brain centres, these systems are serotonergic (5-HT) andnorepinephrinergic, with 5-HT3 receptors and α2 adrenocep-tors being found in the superficial dorsal horn.43 Stimulation ofthese descending inhibitory circuits produces analgesia; themechanism behind this appears to be related to inhibitoryactions on excitatory interneurons and projection neurons.These descending systems may be called the descending painmodulatory system (DPMS).
Examples of the synaptic plasticity of the dorsal horn includethe activity-dependent plasticity of ‘wind-up’, the ‘heterosynap-tic’ central sensitisation as described earlier, the ’homosynaptic’increases in response seen in long-term potentiation andtranscription-dependent central sensitisation.15 Wind-up’s sum-mative increase in dorsal horn neuron output is related to theSP and glutamate-induced change in dorsal horn postsynapticsensitivity.44 Heterosynaptic central sensitisation is partly relatedto transmitters and mediators released from primary afferentsand glial cells, these then act at a distance on dorsal hornneurons to produce long-lasting heterosynaptic potentiation offast synaptic transmission: the two general mechanisms impli-cated in this are the post-translational processing of ion chan-nels/receptors/regulatory proteins and the cell surfaceexpression/trafficking of ion channels.34 Long-term potentiation
is the homosynaptic increase in response to primary afferentinputs and NMDA/AMPA receptor-activated pathways.45 46
Transcription-dependent central sensitisation involves multiplesignalling pathways in the sensory and dorsal horn neurons.45
Figure 2 summarises our current understanding of some of themechanisms behind central sensitisation in the spinal cord.
BrainNociceptive information is transmitted from the spinal cord tothe brain via several different pathways.15 These ascending path-ways include direct projections to the thalamus (spinothalamictract), direct projections to homeostatic control regions (spino-medullary and spinobulbar) and projections to the hypothal-amus/ventral forebrain (spinohypothalamic). The periaqueductalgrey (PAG) and reticular formation are important parts of thespinobulbar system. The thalamus is a key structure in painprocessing and has ascending projections to multiple areasincluding the primary and secondary somatosensory cortices,the anterior insular cortex and the cingulate cortex.47 The sub-jective experience of pain is highly complex and involves otherregions such as the amygdala, prefrontal cortex, cerebellum andbasal ganglia. Key modulatory circuits involving the rostralventromedial medulla (RVM) and PAG exert bidirectionalcontrol over dorsal horn nociceptive transmission.47 Thisnetwork receives numerous direct and indirect inputs from painpathways that include the amygdala, the anterior cingulatecortex and the anterior insula; providing a mechanism for theway in which emotion may affect pain perception. The RVMhas separate descending antinociceptive and nociceptive outputsto the dorsal horn. Figure 3 summarises some of the key painmodulating circuitry.
Where are these receptors located in the shoulder?The peripheral receptors play a pivotal role in the way in whichtissue pathology may generate clinical pain. Therefore, under-standing both the location of the receptors and the types ofreceptor present in the shoulder are of key importance in diag-nosing and treating shoulder pain.
Rotator cuff muscles and tendonsMinaki et al48 investigated the innervation of the rabbit rotatorcuff electrophysiologically and demonstrated a high density ofnociceptors to be present around the rotator cuff ’s humeralinsertion. Supraspinatus was particularly densely innervated withboth mechanoreceptors and nociceptors as shown in figure 4which shows the locations of receptive fields identified in the pos-terior shoulder. In a histological study in rats Backenkohleret al49 showed that Golgi tendon organs were found withintendons where they merge into muscle and in the tendinousinsertions near the joint capsule; it was also shown that themuscle spindles tended to accumulate near the musculotendinousjunction. Some lamellated corpuscles were found in the connect-ive tissue of muscle septa and tendons, in contrast Ruffini corpus-cles were not.
Glenohumeral jointTwo studies using human cadavers have analysed the neurohis-tology of the shoulder joint. Guanche et al50 analysed threecadaveric human shoulders using gold chloride staining andlight microscopy. They found that the superior, middle andinferior glenohumeral ligaments all contained mechanoreceptors(Golgi tendon organs, Ruffini’s endings and Pacinian corpuscles)and free nerve endings. Only free nerve endings were identifiedin the biceps tendon and glenoid labral tissue. Hashimotoet al51 analysed 26 shoulder joints from 13 cadavers usingimmunohistochemistry and light microscopy. A small number offree nerve endings were identified in the innermost layer of thejoint capsule. Many nerve fibres of large diameter were found inboth the anteroinferior and posteriosuperior portions of theoutermost layers of capsule (stratum fibrosum), while nervefibres of various sizes were more numerous in posteriosuperiorand anteroinferior portions of the boundary zone between thelabrum and capsule in all layers.
Figure 4 The receptive fields present in the rabbit rotator cuff. Filledcircles are units with mechanical thresholds greater than 7 g, and opencircles are units with mechanical thresholds less than 7 g.
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Animal studies investigating the innervation of the shoulderjoint have been relatively consistent in their findings.Backenkohler et al49 showed the Ruffini corpuscles were exclu-sively found in the ventral aspect of the joint capsule, whilemost lamellated corpuscles were located in the axillary portionof the joint capsule. Solomonow et al52 examined the distribu-tion of neural elements in the glenohumeral capsule of cats.Again the greatest density of neural elements was found in theinferior aspect of the capsule; nerve fibres, free nerve endings,Golgi tendon organs, Ruffini’s endings and Pacinian corpuscleswere found in all areas of the capsule. Tarumoto et al53 studiedthe glenohumeral capsule in monkeys and again confirmedthis dense inferior capsular innervation, particularly withRuffini-like endings. They also found a high density of smallerpeptidergic fibres that were presumed to be nociceptive, in theposterior half of the capsule; a small number of nociceptivefibres were found to innervate the marginal labrum. Overall, anincreased density of mechanoreceptors in certain areas of theshoulder joint region coincides with zones where sensorycontrol is most important because of increased biomechanicalstress.54 The presence of corpuscular mechanoreceptors in thejoint capsule and glenoid labrum shows their important role ininducing protective reflex actions in phases of extreme or abnor-mal movement.54 55
Subacromial bursaThe subacromial bursa (SAB) is an important structure that hasbeen implicated in the pain of patients with rotator cuff tendi-nopathy and ‘impingement syndrome’. Human tissue from theSAB is readily available because of its frequent removal as partof ‘subacromial decompression’ (SAD) surgery. Numerousstudies have shown that the SAB is richly innervated.56–58 Soiferet al57 examined cadaveric shoulder tissue using IHC and foundthat neural elements to be present in SAB, cuff tendon, bicepstendon and tendon sheath; the nerve supply to the SAB was sig-nificantly denser than that to the other tissues. Tomita et al58
examined tissue from the SAB of patients with varying degreesof cuff tendinopathy. They found that the SAB was innervatedby large numbers of free nerve endings and mechanoreceptors(encapsulated corpuscles); they also found that there was astrong correlation between the density of neural elements at restand shoulder pain at rest, those with higher densities of neuralelements being more likely to experience pain at rest.
Ide et al56 investigated the innervation of the SAB in greatdetail using IHC and their results are shown in figure 5. A largenumber of C and Aδ fibres were found to innervate the SABand they were shown to be immunoreactive to SP and CGRP,confirming their nociceptive role. A variety of mechanoreceptorswere innervated by larger Aβ fibres and these fibres were notimmunoreactive to SP. The Pacinian corpuscles were localised inthe roof of the coracoacromial (C-A) arch side of the bursa,while the Ruffini endings were located at both the greater tuber-osity and C-A side of the bursa; other unclassified mechanore-ceptors were found in the bursa, some of which resembledGolgi-Mazzoni corpuscles. An intriguing study by Gotoh et al24
showed that patients with higher levels of SP in the SAB hadgreater levels of pain, and that SP levels were higher in non-perforated cuff tears versus perforated cuff tears.
Long head of biceps tendonThe long head of biceps tendon (LHBT) is often implicated inshoulder pain and a degenerate LHBT frequently coexists withrotator cuff tendinopathy. Alpantaki et al59 analysed four cadav-eric LHBT in humans using IHC. An extensive neural network
was demonstrated along the tendon, with the densest innerv-ation being present proximally and decreasing distally. Thisinnervation was positive for SP and CGRP, suggesting the pres-ence of thinly myelinated and unmyelinated sensory neurons; itwas also positive for tyrosine hydroxylase, indicating the pres-ence of post-ganglionic sympathetic fibres. Singaraju et al60
compared the neurohistology of the LHBT in patients undergo-ing surgery for pain related to degeneration with that of cadav-eric specimens, none of which had evidence of cuff or LHBTdegeneration. No difference was found in CGRP and SP stainingbetween the two groups but there was a trend towards increasedinflammation and vascularity in the surgical specimens. Theseresults led the authors to conclude that neither the LHBT norits sheath was the sole cause of anterior shoulder pain.Hashimoto et al51 showed that, in the central portion of thelong head of biceps (LHB) tendon, relatively large nerve fibresinserted from the shoulder capsule. Tosounidis et al61 demon-strated by staining for the S-100 protein and neuropeptide Ythat cells with neural differentiation within the LHBT wereincreased in acute injury and hypothesised that this provided amechanism for LHBT-related pain. The function of the LHBtendon and its role in glenohumeral kinematics presently remainonly partially understood62; likewise its role in shoulder painremains controversial and incompletely understood.
C-A ligamentKonttinen et al63 demonstrated the C-A ligament to be aneuralbut the adjacent connective tissue and fat to be richly inner-vated; some of these nerves stained positively for NeuropeptideY (sympathetic marker) and none for SP/CGRP. The rich innerv-ation of the connective tissue adjacent to the coracoacromialligament (CAL) is described above (figure 5). The aneuralnature of the C-A ligament parenchyma has been subsequentlyconfirmed by Tamai et al.64 Tamai et al64 also showed that the
Figure 5 A schematic drawing of the major nerve fibre bundles andthe distribution of sensory nerve endings in the SAB. Double circlesindicate Pacinian corpuscles. Filled circles indicate Ruffini endings.Asterisks indicate free nerve ending plexus. Hatched areas indicateareas where cluster of Golgi-Mazzoni corpuscle-like receptors exists.White circles indicate type II unclassified receptors.
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superficial periligamentous bursal tissue over the CAL was richlyinnervated with nociceptive fibres in patients with rotator cuffdisease and not in controls; they hypothesised that this may beone of the causes of pain in this group of patients.
Neural anatomy of the shoulderThe nerves that contribute to the innervation of the anteriorshoulder joint are the subscapular (C5/6), axillary (C5/6) andthe lateral pectoral (C5/6) (figure 6).65–67 The subscapular nervesarise high from the posterior cord of the brachial plexus andsupply a small portion of the anterior joint. The axillary nerve isthe last nerve of the posterior cord of the brachial plexus beforethe latter becomes the radial nerve. As the axillary nerve coursesacross the subscapularis muscle, it releases its first articularbranch as it runs across the anteroinferior capsule. The axillarynerve divides into two main branches at the lower aspect of sub-scapularis, the medial and lateral branches; the medial branchsupplies the scapular side of the anteroinferior capsule, while thelateral branch supplies the humeral side of the anteroinferiorcapsule. The muscular branch which innervates teres minor, alsoissues a small articular branch at the level of the insertion of thelong head of triceps. The lateral pectoral nerve arises from thelateral cord of the brachial plexus, passes superficial to the axil-lary vessels and pierces the clavipectoral fascia to reach the deepsurface of pectoralis major. A small articular branch arises justbefore it pierces the fascia, this gives off branches to the coracoa-cromial (C-A) and coracohumeral (C-H) ligaments on its way lat-erally. Between these ligaments it then divides into two mainbranches; one passes beneath the C-A ligament to supply theSAB, the other passes across the C-A ligament to supply theanterior portion of the acromioclavicular joint.
The nerves that contribute to the innervation at the posteriorjoint are the suprascapular nerve (SSCN) (C5/6) and axillarynerve (C5/6) (figure 7). The SSCN arises from the upper trunkof the brachial plexus. A large superior articular branch sepa-rates from the main nerve at an average of 4.5 cm proximal tothe transverse scapular ligament,67 together these nerves passunderneath the transverse scapular ligament and enter thesuprascapular notch. After entering the notch, the SSCN turns
laterally and releases a small branch to the coracoclavicular liga-ments. The main articular branch then advances laterallybetween the coracoid and supraspinatus, it divides into two ter-minal branches at this point; one descends to innervate the C-Hligament and the adjacent capsule, the other splits into severalsmall branches which innervate the SAB and the posteriorportion of the acromioclavicular joint capsule. The main SSCNpasses into the suprascapular fossa where it releases a large mus-cular branch supplying the supraspinatus; at the level of thescapular spine a large inferior articular branch separates andtravels obliquely to the posterior capsule. This inferior articularbranch releases several branches which deviate upward anddownward to terminate where the tendon of infraspinatusmerges with the posterior capsule. The suprascapular nerveterminates by supplying infraspinatus. The contribution of theaxillary nerve has been previously described. The sympatheticinnervation of the shoulder joint is from the cervical ganglia(superior, middle and lower) via the grey rami communicantes.
CONSIDERING DRIVERS OF PAIN IN THE DIAGNOSIS ANDMANAGEMENT OF SHOULDER PAINThe traditional triad of history, examination and investigationsare used to guide the clinician towards a reasoned managementplan for the patient’s pain. It is also important to focus on fea-tures of the history and examination which hint at a greaterdegree of central sensitisation being present. A history of thepain radiating down the arm and the presence of ‘light touch’hyperalgesia around the shoulder are both features of centralsensitisation.38 Significant symptoms in the absence of radio-logical abnormality should ring alarm bells; in these cases treat-ing an assumed peripheral pathology surgically may result indisaster as the majority of the pathology is in the higher painprocessing systems.
The lack of reliable diagnostic tests for many shoulderpathologies68 including ‘impingement syndrome’69 70 reflectshow subjective and variable clinical tests may be. This can be
Figure 6 Profile reconstruction of the anterior side of right shoulderjoint in a human fetus. *, Profile line of humeral head; a, articularnerve from the axillary and the musculocutaneous nerves; b, articularnerves from the axillary nerve; c, articular nerve from the subscapularnerve; d, branch of articular nerve from the suprascapular nerve.
Figure 7 Profile reconstruction of posterior side of right shoulderjoint in a human fetus. *, Profile line of humeral head; d, upper branchof the suprascapular nerve; e, lower branch of the suprascapular nerve;f, branches from nerves of supraspinatus and infraspinatus muscles;g, axillary branch to scapular part of capsule; h, axillary branches tohumeral part of capsule.
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explained by mechanosensitivity changing as a result of anyform of peri-articular inflammation with the majority of noci-ceptive fibres (C and δ) showing increased mechanosensitivity;indeed a large proportion of HTM are sensitised such thatthey respond to movements in the working range. This hasbeen confirmed in the shoulder by Yamashita et al71 whoshowed that inflammation peripherally sensitised both low-threshold and high-threshold mechanoreceptors in a rabbitmodel. The classical inflammatory mediators such as bradyki-nin, the prostaglandins and 5-HT3 excite joint afferents andsensitise them to mechanical stimulation. Spinal cord neuronsmay be activated by noxious movements (NS, nociceptive spe-cific) or they may respond with increasing intensity when thestimulus is increased from the innocuous to the noxious range(WDR, wide dynamic range). Both WDR and NS spinal cordneurons show enhanced responses to noxious stimuli appliedin the inflamed joint, and NS neurons show a reduction intheir mechanical threshold so that they now become excited byinnocuous stimuli.
This means that any cause of inflammation in or around theshoulder may give rise to the so-called ‘irritable’ shoulder joint.Therefore, clinically it may be difficult to discriminate betweenrotator cuff tendinopathy and calcific tendinitis or inflammatoryjoint disease, for example; there is a clear lack of clarity withregard to whether common diagnostic tests used in clinicalexamination are useful in differentially diagnosing pathologiesof the shoulder.68 72 Consequently, there has been the moderntrend away from these bedside clinical tests towards radiologicalimaging modalities such as ultrasound and MRI.
Treatments of shoulder painThe treatment of shoulder pain depends largely on the clinicaldiagnosis reached upon and it is beyond the scope of thisarticle to deal with the specifics of all shoulder pathologies. Weintend to focus on the aspects of treatment that are particularlyrelevant to pain processing in this overview. Before embarkingupon a treatment, it is important to adequately assess the sever-ity of the pain, as well as the impact of the pain upon thepatient’s shoulder function and quality of life; in this way anyresponse to treatment can be more objectively measured andquantified. The visual analogue scale (VAS) is one of the manymeasures that can be used to assess pain,73 while there arenumerous shoulder-specific scoring systems74 andquality-of-life measures.75 There are also more specific scoringsystems which can help identify and quantify the neuropathicelement of a patient’s pain such as the pain DETECTquestionnaire.76
Placebo effectAn important obstacle to measuring the effect of any treatment onpain is the significance of the placebo effect, which is ‘the patientresponse to inactive or sham treatments’. Placebo treatments havepowerful analgesic effects and even placebo-controlled randomisedtrials may result in the efficacy of a treatment being misinter-preted.77 The DPMS is crucially important to placebo analgesia.78
Avariety of factors including patient expectation, emotions such asanxiety and mood all have significant effects on the complex neuro-biological process that lies behind placebo analgesia.79 80 Differenttypes of neuropathic pain are affected in different ways by theplacebo effect.81 While different treatments may have hugely differ-ing strengths of placebo effect depending on multiple complexpatient and treatment factors, it has been argued that the placeboeffect of sham surgery is likely to be particularly strong.82
Consequently, the interpretation of treatment effects in shoulderpain is a highly contentious and controversial area. Maximising theplacebo effect is useful for any clinician treating shoulder pain;ensuring that the patient has confidence in the treatment plan andallaying any anxieties are examples of ways in which this can beperformed.
PharmacotherapyThe World Health Organisation’s analgesia ladder is frequentlyused to guide the treatment of pain and has been modified sinceits introduction in 1986.83 Simple agents such as Paracetamoland the non-steroidal anti-inflammatory drugs (NSAIDs) aregenerally first line. Paracetamol has both peripheral and centraleffects in inhibiting prostaglandin synthesis and activating thedescending 5-HT system.84 The NSAIDs inhibit the cyclooxy-genases (COX-1 and COX-2) to varying degrees resulting inboth peripheral and central analgesic effects. Peripherally, theyinhibit the prostaglandin-induced nociceptor sensitisation thatoccurs via TRPV1 and sodium channel activation; centrally,their effects are thought to be partly owing to the inhibition ofthe prostaglandin-mediated glycinergic neurotransmission.
Weak and strong opiates can then be added to the simpleragents in a step-wise fashion. The μ, δ, κ and opioidreceptor-like-1 (ORL1) opioid receptors have been found inhumans.4 The coupling of these receptors to potassium andsodium channels is believed to be the main mechanism bywhich endogenous and exogenous opioids produce analgesia. Ata spinal level the most important mechanism of action is thepresynaptic opioid receptor agonism which leads to a decreasein nociceptive afferent transmitter release; postsynaptic andinterneuron opioid receptor agonism attenuates spinal cordoutputs. Important sites of supraspinal opioid action are thePAG and RVM. Other drugs including certain antidepressantsand anticonvulsants are particularly important in managing
Table 2 A summary of the analgesics that may be used in the management of shoulder pain
Class of drug Examples Simplified mode of action
NSAIDs Paracetamol, diclofenac Cyclooxygenase inhibitionWeak opiates Codeine phosphate, tramadol Peripheral and central opioid receptor agonismStrong opiates Oral morphine solutions Peripheral and central opioid receptor agonismTCAs Amitryptiline, clomipramine, imipramine Blockade of serotonin and norepinephrine reuptake in the CNSSSRIs Fluoxetine, citalopram Blockade of serotonin reuptake in the CNSConventional anticonvulsants Carbamezapine Blockade of voltage-gated sodium channelsOther anticonvulsants Gabapentin, pregabalin GABA agonism/calcium channel inhibition
neuropathic pain.85 Table 2 summarises the classes of drugs thatmay be used in the management of acute and chronic shoulderpain. The decision-making process in analgesic pharmacother-apy involves the consideration of several complex factors includ-ing the nature and the chronicity of the pain; the evolvingspecifics relating to chronic neuropathic pain is a huge topic inits own merit.85 86
Injections and nerve blocksA number of different injection sites have been used in treatingshoulder pain including the glenohumeral joint, the subacromialspace and several nerve blocks. Peripheral injections may bediagnostic, prognostic or therapeutic; they may consist of localanaesthetic with or without steroid. Local anaesthetics aresodium channel blockers and directly block the nerve conduc-tion. The pain-relieving mechanisms of steroids are complex,not only do they have an anti-inflammatory effects, but theyalso appear to reduce nociceptor sensitivity and centralsensitisation.87
The benefits of steroid injections have been demonstrated inboth frozen shoulder and in cuff tendinopathy.88 89 However,the Cochrane review of the use of steroid injections for shoulderpain in frozen shoulder and in rotator cuff disease concludedthat injections may be beneficial, but that their effect may besmall and not well-maintained.90 This conflicting evidencereflects small trial sample sizes, variable methodological qualityand a general heterogeneity.
Nerve blocks are widely used in managing intraoperative andpostoperative pains in shoulder surgery; several nerve blocks orcombinations of blocks are commonly used including the inter-scalene, suprascapular and axillary nerve blocks. The suprascapu-lar nerve block has been shown to be more effective thansubacromial infiltration or placebo after shoulder surgery.91 Thesuprascapular nerve block has also been shown to reduce pain incases of frozen shoulder 1 month following an injection92 and incases of general chronic shoulder pain of multiple aetiologies.93
Pulsed radiofrequency of the suprascapular nerve has also beenreported as an effective treatment of chronic shoulder pain.94
AcupunctureIt is hypothesised that acupuncture relieves pain by activating Aδand possibly C fibres via the mechanical stimulation of needles.Some trials have shown a benefit over placebo in treating shoul-der pain,95 however the benefit could be attributed to thegreater placebo effect of actual acupuncture over sham acupunc-ture. The Cochrane review regarding acupuncture for shoulderpain concluded that there was insufficient evidence to supportor refute it as a treatment.96
Physiotherapy and activity modificationThe proposed analgesic mechanisms of physiotherapy includerotator cuff muscle strengthening, augmenting scapulothoracicmovement, increasing proprioceptive feedback and stretchingtight structures. The exact nature of what shoulder physiother-apy consists of varies widely in the literature; for example, someregimes are patient-led, others more therapist-led, while someare particularly aggressive in terms of provoking pain symptoms.This has been emphasised by the Cochrane review which statedthat the small sample sizes, variable methodological quality andheterogeneity in terms of population studied, physiotherapyintervention employed and length of the follow-up of rando-mised controlled trials of physiotherapy interventions results inlittle overall evidence to guide treatment.97 However, there isevidence to support the use of some interventions in specific
cases,98 99 while physiotherapy has compared favourably withsurgery in some trials.100 Stretching of the posteroinferiorshoulder capsule is an effective treatment for shoulder pain inathletes with an associated internal rotation deficit.101 In thisparticular example the mechanisms behind the pain, the role ofcapsular receptors and the reason for pain improving withstretching remain unclear. Physiotherapy and activity modifica-tion frequently overlap, for example if pain is felt to be relatedto overuse then a reduction in activity levels may be followed bya supervised structured programme of rehabilitation. In someinstances the individual may wish to accept that certain activitiesare no longer possible or that living with a certain level of painis acceptable, this decision is often made having discussed allavailable treatment options with their physiotherapist, doctor orsurgeon.
SurgeryMany of the surgical treatments of shoulder pain involveattempting to switch off the peripheral environmental triggersof pain by attempting to ‘fix’ the underlying ‘causal’ patho-logical process. Defining a causal pathological process is notalways straightforward and this has been emphasised by the con-fusion surrounding the diagnosis and management of ‘impinge-ment syndrome’.69 70 There remains a lack of high-qualityevidence showing that surgery is effective in rotator cuff disease,for example102; the heterogeneous nature of patient groups andtreatment methods make it hard to draw firm conclusions.103
The Cochrane review of surgery for glenohumeral osteoarthritisstated that there was a need for studies comparing shouldersurgery to sham, placebo and other non-surgical treatmentoptions; the ethical and logistical difficulties conducting a trialthat compared shoulder arthroplasty with sham surgery wouldbe considerable. There is emerging evidence that certain surgicaltreatments such as rotator cuff repair result in significant sus-tained benefits in terms of pain and function.104 Certainly morelarge, high-quality randomised controlled trials are needed toanswer these questions surrounding the effectiveness of surgeryin specific shoulder pathologies.
The role of central sensitisation in shoulder pain has recentlybeen explored in relation to ‘impingement syndrome’ andoutcome after SAD.38 Patients with higher levels of punctatehyperalgesia and/or referred pain (features demonstrative ofcentral sensitisation) did significantly worsen in terms of post-operative outcome. Central sensitisation has also been demon-strated in patients with hip and knee osteoarthritis.105 106
Gwilym et al105 demonstrated increased activity in the PAGwith stimulation of the patient’s skin in the areas of theirreferred arthritic pain. Joint arthroplasty can reverse pain-related changes in the thalamus in patients with hip and kneeosteoarthritis, in association with their reduced pain andincreased function following surgery.107 The normalisation ofhyperaesthesia following knee joint arthroplasty has beendemonstrated by Graven-Nielsen et al,37 implying that thecentral pain processes are maintained by peripheral input.
DISCUSSIONThe effective diagnosis and treatment of shoulder pain reliesnot only upon a detailed knowledge of the peripheral patholo-gies that may be present in the shoulder, but also a comprehen-sive understanding of how pain can be generated, propagatedand modified in the human body. Human pain processinginvolves a far higher degree of neuronal plasticity than previ-ously thought. Therefore, the location of receptors and thetypes of receptor present in the shoulder are of key importance
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in explaining this dynamic interaction between peripheral path-ology and pain generation. However, there is still a long way togo in terms of fully understanding the variable relationshipbetween peripheral pathology and perceived pain.
Our enhanced understanding of the molecular mechanismsinvolved in rotator cuff disease is resulting in the developmentof new treatment, for example the use of drugs and scaffolds toaugment rotator cuff tendon repair.108 The role of the nervoussystem and specific neuropeptides in shoulder pain is still emer-ging, but undoubtedly furthering our understanding in thiscomplex area has the potential to unlock some very powerfulnew diagnostic and therapeutic techniques. Genetic testing, bio-marker measurement (both serum and peripheral) and pain-related bedside clinical tests are all examples of methods whichcan potentially be used to aid diagnosis and guide therapeutics.As the genetic component of shoulder pain is unravelled it mayeven be possible to determine which patients are particularlypredisposed to problems so that they could be targeted withpreventative treatments.
One new avenue for treatment is the pharmacologicalmanipulation of the nervous system to modify the perception ofpain. This may be performed peripherally, centrally or by a com-bination of the two. The early results of anti-NGF treatment ofpain in knee osteoarthritis showed promise before trails wereabandoned owing to serious neuropathic complications,109 dem-onstrating both the potential benefits and the pitfalls of newanalgesic pharmacotherapies. SP has been implicated in thepathogenesis of tendinopathy in animal models110 111 and inhumans.112 This raises the possibility of using SP antagonism totreat tendinopathy; in contrast, SP injections have shown anearly promise in an animal model of tendon repair.113
The complex role of neuronal mediators like SP is demon-strated by its positive and negative effects in these studies,underlining how far we are from a full understanding of thedynamic role of the nervous system in painful musculoskeletalconditions. However, as this complexity is unravelled there isthe potential for pharmacological interventions to be used inisolation or in combination with other treatments such asphysiotherapy and surgery to create a multimodal approachwhich addresses all areas (peripheral and central) contributingto a patient’s shoulder pain.
Contributors All authors have contributed to the drafting and finalisation of themanuscript.
Competing interests The authors of this work are funded by the MusculoskeletalBiomedical Research Unit of the National Institute for Health Research (BD, SG andAC), the Jean Shanks Foundation (BD) and the Lord Nuffield Scholarship forOrthopaedic Surgery (BD).
Provenance and peer review Not commissioned; externally peer reviewed.
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